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P23 Essential but partially redundant roles for POU4F1/BRN-3A and POU4F2/BRN-3B transcription factors in the developing heart
  1. L Maskell,
  2. K Qamar,
  3. TA Hawkins,
  4. VS Budhram-Mahadeo
  1. Institute of Cardiovascular Science, UCL Rayne Building, London, UK


Rationale Transcription factors (TFs), which control cardiac gene expression, are important regulators of normal heart development and aberrant expression can contribute to congenital heart defects (CHD), associated with embryonic or neonatal lethality. Brn-3a/POU4F1 and Brn-3b/POU4F2 TFs are expressed in hearts and isolated cardiomyocyte cultures. Studies in injured mouse heart showed that Brn-3b promoted apoptosis if coexpressed with p53 whereas Brn-3a protected against p53 mediated death. Their roles in the developing heart are not known so formed the basis for these studies.

Results Brn-3a and Brn-3b displayed partial compensatory effects in developing mouse hearts because increased Brn-3b in Brn-3a knock-out (KO) hearts supported survival during gestation, whereas double KO mutants (Brn-3a-/-:Brn-3b-/-) showed early embryonic lethality (e9.5). Brn-3a and Brn-3b are highly conserved (>80%) between mouse and zebrafish (ZF) so studies with morpholino oligonucleotides (MO) were used to show that reducing both Brn-3a and Brn-3b caused significant cardiac defects (abnormal looping and valve formation) in double morphants, not seen in single or control morphants. However, increased Brn-3b and its target genes e.g. cyclin D1 in Brn-3a KO mutant hearts during mid-gestation correlated with hyperplastic growth in valve/septum. At later stages, loss of Brn-3a and increased Brn-3b resulted in cardiomyocyte apoptosis, ventricular wall/septal thinning/non-compaction that may contribute to death of Brn-3a KO mutants soon after birth.

Conclusion Our results suggest essential but partially redundant roles for Brn-3a/POU4F1 and Brn-3b/POU4F2 transcription factors (TFs) in the developing heart.

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